Cancer Gene Discovery to Identify Targetable Targets

癌症基因发现以确定可靶向的靶点

• 批准号: 9321279
• 负责人: CARLO M CROCE
• 金额: $ 92.4万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-11 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321279
• 关键词: 13q14; Affect; Apoptosis; Award; BCL-2 Protein; BCL2 gene; Binding; Burkitt Lymphoma; Cachexia; Cells; Chromatin Structure; Chromosomes; Code; DNA Sequence Alteration; Dendritic Cells; Disease; Endosomes; Follicular Lymphoma; Gene Family; Gene Mutation; Genes; Germ-Line Mutation; Homologous Gene; Human; Human Genome; IL6 gene; Immunoglobulins; In complete remission; Journals; Knockout Mice; MLL gene; MYC gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; MicroRNAs; Mus; Mutation; Myoblasts; Oncogenes; Pathogenesis; Pathway interactions; Patients; Peer Review; Pharmaceutical Preparations; Proteins; Publishing; Research Personnel; Role; Scientist; Somatic Mutation; T-Cell Leukemia; T-Cell Receptor; T-Lymphocyte; TLR8 gene; Transgenic Mice; Tumor Suppressor Genes; Untranslated RNA; Work; cancer genetics; gene discovery; indexing; macrophage; microvesicles; novel; programs; prototype; public health relevance; receptor; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Previously, I was awarded the Outstanding Investigator award for two terms before the Program at NCI was discontinued. I have continued to be extremely productive to these days. My H index is 179 and I am one of the most cited scientists in the world. I have published more than 1000 articles in peer reviewed journals. I have also made many important discoveries in cancer genetics and have identified and characterized many cancer genes. My discoveries that changed the ways to think about cancer, I believe, are: the demonstration of the juxtaposition of the MYC oncogene to the immunoglobulin loci and its dysregulation in Burkitt lymphoma, the first demonstration of the specific gene alterations in human cancer. The discovery of the BCL2 gene and its involvement in follicular lymphoma and in other malignancies. The Bcl2 protein is now targeted by ABT199, a drug of Abbott that causes complete remission in patients with CLL. BCL2 is the prototype of a large family of genes that control programmed cell death, or apoptosis. The discovery of ALL1, now renamed MLL1, a gene involved in more than 50 different translocations in ALL and AML. Its dysregulation in cancer affects chromatin structure. I also discovered the partial duplication of ALL1 (MLL1) in AML. I also discovered TCL1, which is responsible for 98% of human pre T cell leukemias, and that this gene is dysregulated in most of the aggressive CLLs. I have also discovered the role of translocations involving the T cell receptor in T cell malignancies. I also generated transgenic and KO mice to validate the oncogenes and tumor suppressor genes we discovered. It was thought that all cancer genes were encoding protein products. The dogma was that only protein coding genes that represent only 2% of the human genome were important and the remaining 98% was "junk". This view was shattered by my discovery in 2002 that CLL is caused by the loss of two microRNA genes on chromosome 13q14, miR-15a and miR-16-1. Thus genes encoding non coding RNAs can also be involved in cancer pathogenesis. We also found that these two microRNAs target BCL2, the gene I discovered in 1984. We also discovered germline and somatic mutations in microRNA genes in human malignancies and that microRNAs are dysregulated in all cancers, primarily because several of them are downstream targets of pathways responsible for oncogenesis. More recently, we discovered that tumors such as lung cancer and pancreatic cancer secrete microvesicles that fuse with macrophages and dendritic cells. MiR-21 that is contained in such microvesicles is internalized, reaches the endosomes of the recipient cells and binds and activates Toll Like Receptor 8 in humans and 7 (it's homologue) in the mouse, activating the receptor. Then NF-κB is activated and IL6 and TNFalpha are secreted, facilitating tumor spreading and metastatic disease. This year we showed that fusion of microvesicles with myoblasts causes cachexia.